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An essential role for bacterial nitric oxide synthase in Staphylococcus aureus electron transfer and colonization

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Nitric oxide (NO) is a ubiquitous molecular mediator in biology. Many signalling actions of NO generated by mammalian NO synthase (NOS) result from targeting of the haem moiety of soluble guanylate cyclase. Some pathogenic and environmental bacteria also produce a NOS that is evolutionary related to the mammalian enzymes, but a bacterial haem-containing receptor for endogenous enzymatically generated NO has not been identified previously. Here, we show that NOS of the human pathogen Staphylococcus aureus, in concert with an NO-metabolizing flavohaemoprotein, regulates electron transfer by targeting haem-containing cytochrome oxidases under microaerobic conditions to maintain membrane bioenergetics. This process is essential for staphylococcal nasal colonization and resistance to the membrane-targeting antibiotic daptomycin and demonstrates the conservation of NOS-derived NO-haem receptor signalling between bacteria and mammals.

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Figure 1: Regulation of O2 respiration by saNOS.
Figure 2: Delayed induction of SrrAB-regulated genes and nitrate respiration in the absence of saNOS.
Figure 3: Maintenance of membrane potential (Δψ) by saNOS.
Figure 4: Promotion of daptomycin resistance by saNOS.
Figure 5: Role of saNOS in mouse nasal colonization.
Figure 6: saNOS maintains Δψ under microaerobic conditions by regulating O2 and NO3 respiration.

Change history

  • 14 July 2017

    In the PDF version of this article previously published, the year of publication provided in the footer of each page and in the 'How to cite' section was erroneously given as 2017, it should have been 2016. This error has now been corrected. The HTML version of the article was not affected.


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The authors thank D. Prunkard in the UW Pathology Flow Cytometry facility for help with the flow cytometer set-up and data collection, and E. Nudler for providing wild-type and bsNOS mutant B. subtilis strains. This work was supported by NIH grants AI44486, AI55396 and AI123124 (to F.C.F.) and by NIH training grant support AI055396 (to S.R.M.).

Author information




Conceptualization was provided by T.L.K. and F.C.F., and the methodology was designed by T.L.K., S.R.-M., J.M.P., S.J.L. and F.C.F. Investigations were carried out by T.L.K., S.R.-M., D.V.T., E.N.S., S.J.L. and F.C.F., and data analysis by T.L.K., S.R.-M., S.J.L. and F.C.F. The original draft of the manuscript was written by T.L.K. and F.C.F., and was reviewed and edited by T.L.K., S.R.-M., J.M.P., S.J.L. and F.C.F. Funding was acquired by F.C.F.

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Correspondence to Ferric C. Fang.

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The authors declare no competing financial interests.

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Supplementary Figures 1–4, Supplementary Methods, Supplementary Table 1, Supplementary References. (PDF 2804 kb)

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Kinkel, T., Ramos-Montañez, S., Pando, J. et al. An essential role for bacterial nitric oxide synthase in Staphylococcus aureus electron transfer and colonization. Nat Microbiol 2, 16224 (2017).

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